This invention relates generally to a reagent and method for coupling amines with carboxylic adds to form amides.
Reacting an amine with a carboxylic acid to form a new species having an amide linkage is well known to the chemical arts. The reaction is generally implemented with a dehydrative coupling reagent.
Within the last thirty years solid phase synthetic procedures for coupling mines and carboxylic acids, for example to make peptides and polypeptides, have become well known in the chemical arts. The Merrifield solid phase synthesis, in both manual (JACS, 85, 2149, 1963) and automated (Science, 150, 178, 1965) forms is perhaps the oldest and best known method and functions by growing a polypeptide chain which is bound on an insoluble polymer. The chain is grown amino acid by amino add, with each new residue being added, in the presence of a coupling reagent, from a solution of the N-blocked acid. By attaching the growing peptide chain to an insoluble polymer, the Merrifield synthesis advantageously provides the peptide in a convenient form to be filtered and washed free of reagents and by-products.
In general, carbodiimides are known to be coupling reagents for the formation of amide linkages. In some instances a carbodiimide coupling reagent has been incorporated into a polymer, in what is in effect a variation on the Merrifield technique, to form a solid phase coupling reagent. For example, Wolman et. al., Chem. Commun., 629, (1967) report the use of an insoluble polycarbodiimide as a condensing agent in peptide synthesis, with best results reportedly obtained using polyhexamethylene-carbodiimide made by the catalytic decarboxylation of 1,6-diisocyanate hexane. This solid phase coupling reagent thus incorporates carbodiimide linkages as part of the polymer backbone.
Weinshenker et. al., Tetrahadron Lett., 3281 (1972) and Org. Synth., Coll. Vol. VII, 951, (1990) report synthesizing a polymeric carbodiimide by a detailed procedure involving (1) converting crosslinked chloromethylated polystyrene to polystyrene having pendant phthalimidomethyl groups; (2) converting the phthaiimidomethyl groups to aminomethyl groups; (3) treating the pendant aminomethyl groups with isopropylisocyanate to thereby make the corresponding isopropylureamethyl groups; and (4) dehydrating the urea moiety/to convert the pendant isopropylureamethyl groups to isopropyl carbodiimidomethyl groups. In contrast to Wolman et. al. as discussed above, the Weinshenker polymeric carbodiimide incorporates carbodiimide units as pendant groups rather than as part of the polymer backbone.
Nutt, U.S. Pat. No. 4,102,877 discloses using a Weinshenker-type of resin-bound carbodiimide in the cyclization of linear peptides.